Tamoxifen, an estrogen receptor alpha (ERa) antagonist, is an effective chemopreventive agent against breast cancer. The soy phytoestrogens genistein and daidzein selectively bind to ERbeta. Theoretically, these soy phytoestrogens (also known as soy isoflavones) may enhance or negate tamoxifen's chemopreventive effects. Women at high risk for developing breast cancer, or breast cancer patients with ER-positive tumors, are now treated with tamoxifen to prevent primary breast tumors or the development of recurrences, respectively. However, it is presently uncertain if these women are benefited or harmed by consuming soy products, or by taking phytoestrogens as supplements. Our recent preliminary studies in the dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis rat model suggest that soy compound(s), possibly phytoestrogens, enhance tamoxifen's chemopreventive action. We hypothesize that soy phytoestrogens (or other soy compounds) enhance tamoxifen's antitumor action. The proposed mechanism of action is that tamoxifen, acting mainly as an ER-alpha antagonist, and soy phytoestrogens acting mainly as ER-beta-selective agents, exert antiproliferative and/or antioxidant effects against mammary carcinogenesis. We propose to elucidate the mechanism(s) whereby tamoxifen and phytoestrogens exert their antitumor effects by examining both ER-dependent and ER-independent signaling pathways. The specific aims are: (1) Determine if the antitumor effects of 4-hydroxytamoxifen (4-OHT) and soy phytoestrogens are mediated through the estrogen response element (ERE), the activator protein-1 (AP-1) pathway, or the G-C rich simianvirus-40-protein-1 (SP-1) pathway. (2) Determine if the antioxidant response element (ARE) mediates the individual and combined effects of 4-OHT and soy phytoestrogens. (3) Evaluate how the combination of tamoxifen and soy phytoestrogens affects tumor recurrence in the DMBA/rat mammary carcinogenesis model, and the development of tamoxifen-stimulated mammary tumors in athymic mice. Increasing numbers of women are taking tamoxifen together with soy or soy isoflavones, yet little is known about the effects of this combination. This study will systematically explore their interactions to determine their safety and efficacy.